1. Field of the Invention
Embodiments of the invention pertain generally to the field of Convection Enhanced Delivery (CED) of therapeutic and/or diagnostic agents (hereinafter referred to as, but not limited per se to, “drugs”). More particularly, embodiments of the invention pertain to microfabricated, microfluidic CED devices, manufacturing methods, and methods for the convection enhanced delivery of a drug.
2. Description of Related Art
Numerous localized drug delivery strategies have been developed to circumvent the blood brain barrier. For example, the insertion of polymeric implants that release drugs slowly into the surrounding tissue has been reported to be successful in treating tissues locally. These implants also can be effective in treating intracranial tumors with local chemotherapy because high drug doses can be delivered to the tissue surrounding the implant. However, it is known that the distance that a drug penetrates into the tissue after release depends on the relative rates of drug transport and drug elimination. When diffusion is the dominant transport mechanism, the concentration of the drug decays exponentially with distance from the implant. In many instances, only the tissue within a few millimeters of the implant is exposed to a therapeutically useful drug concentration. In this case, treatment may be enhanced by alternative delivery methods that increase the penetration distance of the drug into tissue and eliminate the rapid decay in concentration with distance that is characteristic of diffusion mediated transport.
Convection-enhanced drug delivery (CED) uses direct infusion of a drug-containing liquid into tissue so that transport is dominated by convection. By increasing the rate of infusion, the convection rate can be made large compared with the elimination rate in a region of tissue about the infusion point. Thus, CED has the potential of increasing the drug penetration distance and mitigating the decay in concentration with distance from the release point. In addition, CED may overcome limitations of traditional treatments for brain tumors caused by the large tumor size and the difficulty of delivering therapeutic agents into their dense tissue.
Convection-enhanced drug delivery has been tested extensively in animals and humans. Small molecules, proteins, growth factors, and nucleotides reportedly have been infused into animal models for therapeutic and imaging purposes. Chemotherapy agents, viral vectors, and proteins reportedly have been infused into humans in clinical trials. Initial studies reportedly were confined to infusion in the homogenous, gray matter bodies of the brain. Other published studies have concentrated on the globus pallidus internus, peripheral nerves, tumors, and the brainstem. The results of these studies indicate that convection can be used to distribute molecules, regardless of their size, throughout most regions of the brain. However, it can be difficult to control the distribution of infused molecules when characteristics of the tissue vary within the treatment region, such as in heterogenous tumors and near white matter tracts in the brain. Clinical trials for treating brain tumors have reported similar problems in tracking and predicting the distribution of infused chemotherapy agents.
CED involves inserting a small cannula or needle into an afflicted area and infusing drug or imaging solutions at a specified flow rate. This cannula is most often a stainless steel needle ranging from 20 to 32 gauge (ga) in size. In prior reported studies, flow rates ranged from 0.1 to 10 μL/min and were controlled with an external syringe pump. At flow rates greater than 1 μL/min, backflow of infused solutions up the outside of the needle shaft has been reported. Apparently, at sufficiently high flow rates, the tissue separates from the needle and injected fluid flows preferentially along the separation. Backflow reduces control over drug delivery because infused solutions can flow out of the brain or into highly permeable white matter tracts surrounding the infusion site. The separation that allows backflow can be controlled by adjusting the flow rate and the size of the needle. Another problem encountered with needles is an unexpectedly large pressure at the needle tip at the start of an infusion. The large pressure may indicate that the tip of the needle is partially or fully occluded when it is inserted into the brain.
Microneedles with on-chip flow meters and pumps provide fluid flow control and minimize reagent volume. The implantation of silicon devices has been extensively characterized for cortical neural prosthetics. Some implanted devices have recorded electrical signals for up to one year in vivo. Other neuroscience applications for which microfluidic devices may be useful include measuring cerebrospinal fluid flow, infusing neurotransmitters and neurotrophic factors, and studying addiction mechanisms. For example, L-glutamate is the most ubiquitous excitatory neurotransmitter in the mammalian central nervous system (CNS). Its presence has been linked with various brain disorders including Parkinson's disease, schizophrenia, stroke and epilepsy. The measurement of functional levels of L-glutamate in the CNS is thus of interest. Intracranial microdialysis is a widely reported technique used for measuring L-glutamate and other amino acids in CNS tissues in vivo. It involves identification of chemicals of interest in the dialysis sample by using modern analytical techniques such as HPLC, with electrochemical detection or fluorescent detection. There are questions, however, about the reliability of such measures for studies of release and uptake of neuronal glutamate. Poor spatial resolution and slow time resolution attributed to the technique may result in inadequate sampling of neurotransmitters with fast kinetics like L-glutamate. L-glutamate is reportedly thought to be rapidly removed from the extracellular space by glutamate transporters located on neurons and glia in order to maintain low and non-toxic extracellular levels. Reported recent advances in microdialysis, combined with capillary electrophoresis separation and quantitation, allow for sampling of L-glutamate every few seconds. However, there has been a need for advancements in technology to record glutamate dynamics, second-by-second, with a spatial resolution of microns analogous to electrophysiological recordings of neuronal activity.
Reported voltammetric techniques coupled with microelectrodes have shown promise for measuring changes of neurotransmitters such as L-glutamate in the extracellular space of the brain. However, the microelectrodes previously reported have suffered from problems associated with the size of the recording microelectrodes, the microelectrode response time and the lack of ability to mass produce the microelectrodes. Burmeister et al., Journal of Neuroscience Methods, 119 (2002) 163-171 report the refinement of a ceramic-based microelectrode fabricated using photolithographic techniques for rapid measures of L-glutamate in CNS tissues.
In regard to drug delivery techniques, many promising treatments for brain diseases involve nanoparticles as drug or gene carriers. The blood-brain barrier prevents most particles from penetrating into the brain, making intracranial infusions, or convection-enhanced delivery (CED), an attractive drug delivery strategy. However, transport of particles through the extracellular space of tissues is hindered by the large size of nanoparticles (10-100 nm), which are much larger than small molecule drugs or therapeutic proteins that more easily penetrate the brain extracellular matrix (ECM). Nanoparticles may be able to penetrate brain tissue provided that particles are less than 100 nm in diameter, are neutral or negatively charged, and are not subject to rapid elimination mechanisms.
The published literature reports studies of CED of liposomes in animal tumor models. Initial studies involving two sizes of liposomes showed that 40 nm liposomes distributed throughout the striatum of rats, but that 90 nm liposomes were confined to regions near the infusion point. Infusion of polystyrene particles showed similar effects of particle size. The distribution volume for 100 nm polystyrene particles was about half of that for 40 nm particles. The effective pore size of the extracellular matrix of gray matter has been estimated to be between 38 and 64 nm, which may explain why larger particles have difficulty moving through the ECM. Other factors also may limit the extent of particle penetration in the brain. Nanoparticles can be entrained in white matter and in necrotic zones of brain tumors. Liposomes can accumulate in and move through perivascular spaces. Transport through perivascular spaces is thought to be an important part of fluid removal from the brain. It has been suggested that preferential transport through the perivascular space is responsible for some of the side-effects reported from CED and gene therapy clinical trials.
It may be possible to increase the effective pore size and enhance the penetration of nanoparticles in tissue by selective enzymatic digestion of some ECM components. For example, Netti et al., Role of extracellular matrix assembly in interstitial transport in solid tumors, Cancer Res. 60 (2000) 2497-2503 reported a 100% increase in the diffusivity of IgG following collagenase treatment of xenografted tumors. Unlike most other tissues, the extracellular matrix of the brain has a low content of fibrous matrix proteins such as collagen. Brain ECM primarily consists of a family of proteoglycans called lecticans and the two components to which they bind, tenascins and hyaluronan (HA). These three macromolecules form a ternary structure in the extracellular space of the adult brain. HA serves as the structural backbone of the brain ECM, and highly charged chondroitin-sulphate proteoglycans (CSPG) side chains anchor the ECM to cells and blood vessels. HA and CSPG can be selectively degraded in the brain by hyaluronidase and chondroitinase, respectively. However, some hyaluronidases cleave glycosidic bonds in CSPGs as well as those in HA.
In view of the known related art, the inventors have recognized a need for, among other things, improving upon related art devices and techniques directed at CED of drugs; eliminating or mitigating the known problems and drawbacks associated with related art devices and techniques directed at CED of drugs; providing novel devices and techniques for CED of drugs; and, identifying and implementing applications for such novel devices and techniques directed at CED of drugs.
These and other objects, as well as benefits and advantages, provided by the various disclosed embodiments, will become more apparent to persons skilled in the art based on the following description and figures associated therewith.